Non-insulin-dependent diabetes mellitus (NIDDM) is a rapidly emerging health problem of American Indians. Consequently, diabetic complications, including renal, heart, and eye disease, peripheral neuropathy, infections, and lower-extremity amputations, have become common sources of death and disability in these populations. Among the Navajo Tribe, the largest American Indian tribe in the United States, deaths attributed to diabetes occur at twice the rate of the general United States population, and in the Pima Indians, who have the world's highest reported rate of NIDDM, deaths from diabetes occur at 12 times the rate of the general U.S. population. Impaired glucose tolerance (IGT) is an abnormal condition defined by a glucose tolerance test. Persons with IGT do not have the symptoms or complications of diabetes, but are at increased risk of developing NIDDM. Obesity and the degree of hyperglycemia predict which persons with IGT are most likely to deteriorate to NIDDM. Thus, treatments to reduce obesity and hyperglycemia might reduce the incidence of diabetes in persons with IGT. Planning for a large, multi-center randomized clinical trial is proposed that will determine whether treatment of obese, sedentary American Indian adults with impaired glucose tolerance (IGT) will prevent or delay the development of NIDDM. The proposed study will be conducted at three centers located in Arizona, Montana, and New Mexico, will include 1050 subjects, and will require one year of planning. Navajo, Sioux, Assiniboine, Pima, and Tohono O'odham Indians, who have very high incidence rates of NIDDM, will be invited to participate. Subjects will be allocated to metformin or placebo groups and to a standard or special die-exercise treatment for 5 or 6 years in a 2x2 factorial design (i.e., each of the four combinations of diet-exercise and drug treatment will be represented). The study will be designed to detect meaningful effects of either the diet- exercise program or drug treatment, or both, on the incidence of diabetes in these high-risk populations.